Update PCSK9 trials. Vascular Rounds MUMC

Transcriptie

1

2 Update PCSK9 trials Vascular Rounds MUMC 16 mei 2017 Frank L.J. Visseren

3 Disclosures Voor bijeenkomst mogelijk relevante relaties: Sponsoring of onderzoeksgeld Honorarium of andere (financiële) vergoeding ZonMw, Wellerdieck-de Goede fonds, Leatare founda8on, Vrienden UMC Utrecht, Nederlandse Harts8ch8ng Geen Aandeelhouder Nee Andere relatie, namelijk Fase II/III klinisch onderzoek met vrijwel alle denkbare lipiden-verlagende middelen (o.a. Sanofi, Medicines Company, Amgen, Pfizer, Eli Lilly, Merck, ISIS) Lid richtlijn commissies: CVRM, addendum CVRM bij ouderen, addendum (erfelijke) dyslipidemie

4 PCSK9 Proprotein convertase Subtilisin/kexin Type 9 Serine protease

5 PCSK9; how it started Affected family members with: Total cholesterol >90th percentile Tendon xanthomas CHD, early MI, Stroke Nat Genet 2003;34:

6 PCSK9-i and incident diabetes NEJM 2016:375:

7 Mutations in PCSK9-i or HMGCR genes and risk of MI NEJM 2016:375:

8 Mutations in PCSK9-i or HMGCR genes and risk of MI or DM2 NEJM 2016:375:

9 Mutations in PCSK9-i or HMGCR genes and risk of MI NEJM 2016:375:

10

11 GLAGOV trial JAMA 2016;316:

12 GLAGOV trial Screening and placebo run-in period Clinically indicated coronary angiogram IVUS based on coronary angiogram results SC injection of 3 ml placebo Up to 4-week lipid stabilization period Assigned to background statin therapy Randomization 1:1 to study drug Placebo SC every month Evolocumab 420 mg SC every month End Of Study 2 4 weeks Maximum 6 weeks Study visits: D1 W4 W12 W24 W36 W52 W64 W76 W78 W80 EOS Study drug was administered monthly at home or in the clinic Last Last dose of IVUS study procedure drug JAMA 2016;316:

13 Intravascular Ultrasound (IVUS) PAV = Σ(EEM area lumen area ) Σ(EEM area ) X 100 Leading edge of the EEM Leading edge of the lumen JAMA 2016;316:

14 GLAGOV trial JAMA 2016;316:

15 GLAGOV trial: LDL-c levels JAMA 2016;316:

16 GLAGOV: primary and secondary outcomes JAMA 2016;316:

17 GLAGOV trial JAMA 2016;316:

18 NEJM 2017;376:

19 NEJM 2017;376:

20 NEJM 2017;376:

21 NEJM 2017;376:

22 NEJM 2017;376:

23 NEJM 2017;376:

24 NEJM 2017;376:

25 NEJM 2017;376:

26

27 NEJM 2017;376:

28 Summary FOURIER

29

30

31

32

33

34

35

36

37 Efficacy and safety of alirocumab in reducing lipids and cardiovascular events (ODYSSEY LONG TERM study) Robinson JG et al, NEJM 2015;372:

38 Robinson JG et al, NEJM 2015;372:

39 Efficacy and safety of alirocumab in reducing lipids and cardiovascular events (ODYSSEY LONG TERM study) Robinson JG et al, NEJM 2015;372:

40 Eur Heart J 2016:37:

41 Eur Heart J 2016:37:

42 Eur Heart J 2016:37:

43 OSLER longterm follow up JAMA Cardiol 2017, online March 14

44 OSLER longterm follow up JAMA Cardiol 2017, online March 14

45 IMPROVE-IT study Eur Heart J 2016;37:

46 ESC guidelines on cardiovascular disease prevention: lipid-lowering therapy Recommendations Class Level Prescribe statin up to the highest recommended dose or highest tolerable dose to reach the goal. In the case of statin intolerance, ezetimibe or bile acid sequestrants, or these combined, should be considered. If the goal is not reached, statin combination with a cholesterol absorption inhibitor should be considered. If the goal is not reached, statin combination with a bile acid sequestrant may be considered. I IIa IIa IIb A C B C In patients at very high-risk, with persistent high LDL-C despite treatment with maximal tolerated statin dose, in combination with ezetimibe or in patients with statin intolerance, a PCSK9 inhibitor may be considered. IIb C Eur Heart J 2016;37:

47 NEJM 2017;376:

48 PCSK9 inhibition by RNAi NEJM 2017;376:41-51.

49 ORION trial NEJM 2017;376:

50 ORION trial NEJM 2017;376:

51 ORION trial NEJM 2017;376:

52 Vergoedingscriteria PCSK9-i

53 Conclusies PCSK9-remming verlaagt LDL-c en verlaagt CV risico in 2 grote trials > pa8enten FOURIER resultaten beves8gingen/ondersteunen de bestaande vergoeding voor PCSK9-i. Nieuwe manieren van PCSK9 (en dus LDL-c) verlaging in aantocht Welke pa8ënten komen m.i. met name in aanmerking voor (verdere) LDL-c reduc8e met PCSK9-i: pa8ënten met progressie van vaatlijden ondanks op8male lipidenbehandeling. hoogrisico pa8ënten (bv. DM2, FH) die vaatlijden ontwikkelen ondanks op8male lipiden-behandeling OF vaatlijden hebben en streefwaarde van LDL-c niet halen. pa8ënten met cholesterol-ziekte (FH) die streefwaarde voor LDL-c (ruim) niet halen